The technical field of this invention concerns methods and means for detecting vascular diseases, such as atherosclerotic lesions, and in particular, methods and means employing labeled, target-seeking, biologically active molecules to detect abnormal arterial structures or compositions.
Atherosclerosis is a disease which causes the thickening and hardening of the arteries, particularly the larger artery walls. It is characterized by lesions of raised fibrous plaque which form within the arterial lumen. The plaques are most prevalent in the abdominal aorta, coronary arteries or carotid arteries and they increase progressively with age. They commonly present dome-shaped, opaque, glistening surfaces which bulge into the lumen. A lesion typically will consist of a central core of lipid and necrotic cell debris, capped by a collagen fibromuscular layer. Complicated lesions will also include calcified deposits and exhibit various degrees of necrosis, thrombosis and ulceration.
The deformities of the arterial lumen presented by the plaque and associated deposits result in occluded blood flow, and ultimately ischemic heart disease, stroke, or diseases of other organs, if untreated. At present, coronary atherosclerosis is still the leading cause of death in the United States, claiming the lives of over a half million Americans annually, roughly twice as many as are killed by cancer.
Unfortunately, the early stages of atherosclerosis and related vascular diseases are most often clinically silent. Since lifestyle changes, drug therapy and other means exist for delaying or reducing vascular occlusion or the stresses on various body organs which result from atherosclerotic lesions, the early detection of atheromatous plaque in the vascular system would be of considerable value in permitting preventive intervention at a time when it can be most effective.
Arteriography, the conventional approach to assessing vascular disease, involves catheterization and the injection of radioopaque substances into the bloodstream in order to image obstructions in the arteries. This procedure involves significant morbidity, in that infection, perforation of the artery, arrhythmia, stroke, infarction and even death can occur. Because of the risks involved, arteriograms typically are reserved for individuals with advanced or acute atherosclerotic disease.
A variety of less invasive techniques for the diagnosis of vascular diseases have been proposed. These techniques include plethysmography, thermography and ultrasonic scanning For a further review of these techniques, see an article by the present inventor and a colleague, Lees and Myers, "Non-Invasive Diagnosis of Arterial Disease", Vol. 27 Annals of Internal Medicine, pp. 475-509 (1982), herein incorporated by reference.
Another non-invasive approach to the diagnosis of vascular disease which has been proposed by the present inventor involves the labeling of low density lipoproteins (LDLs) with radioisotopes and the administration of such labeled LDLs to a patient. Because atherosclerotic plaques tend to take up lipoproteins from the blood circulating in the arteries, the labeled LDLs can be imaged with a gamma camera or other radiation detector to provide information on the location and extent of plaque in the vascular system. For details on this approach, see U.S. Pat. No. 4,660,563 "Method and Means for Detection of Arterial Lesions" dated Apr. 29, 19 and U.S. Pat. No. 4,647,445 "Improved Radiolabelled Lipoproteins and Methods for Making Same" dated Mar. 3, 1987, both of which are also incorporated herein by reference.
One disadvantage to the use of labeled LDL's is that the patient's own blood typically is the most appropriate source of lipoproteins, and this entails a two or three day delay between the beginning and the end of the study. Often, such a time period is not available for sick patients. Furthermore, labeled LDLs image acute, rapidly growing atherosclerosic lesions, as reported by the present inventor and colleagues, Lees et al., Journal of Nuclear Medicine, Vol. 24, pp. 154-156, 1983, and herein incorporated by reference. The need exists to localize less rapidly growing artherosclerosic lesions which may not take up LDLs rapidly enough to be imaged. Consequently, there exists a need for better non-invasive techniques and reagents capable of detecting vascular diseases, locating arterial lesions and quantifying the extent of vascular injury.